EP0025897B1 - Peptides et procédé pour leur préparation - Google Patents

Peptides et procédé pour leur préparation Download PDF

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Publication number
EP0025897B1
EP0025897B1 EP80105158A EP80105158A EP0025897B1 EP 0025897 B1 EP0025897 B1 EP 0025897B1 EP 80105158 A EP80105158 A EP 80105158A EP 80105158 A EP80105158 A EP 80105158A EP 0025897 B1 EP0025897 B1 EP 0025897B1
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Prior art keywords
val
glu
tyr
lys
obu
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German (de)
English (en)
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EP0025897A2 (fr
EP0025897A3 (en
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Rolf Prof. Dr. Geiger
Wolfgang Dr. König
Gerd Dr. Johnscher
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Hoechst AG
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/66—Thymopoietins
    • C07K14/662—Thymopoietins at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/18—Thymus derived hormone or factor; related peptides

Definitions

  • Thymosin ⁇ 1 Thymopoietin
  • FTS facteur Thymique serique
  • the acidic function in the characteristics reproduced above is performed by L- or D-glutamic acid as well as D-aspartic acid and da-aminoadipic acid
  • the hydrophobic region can comprise 1 to 2 amino acids or their amides or esters, where S -Ile or S -Val, as the central area, gives the peptides a particularly favorable quality of action.
  • the alkanoyl radical can be a formyl to hexanoyl radical, the aroyl radical benzoyl, which is optionally substituted by methyl, methoxy or chlorine, the aralkanoyl radical phenacetyl, cinnamoyl, dihydrocinnamoyl, phenoxyacetyl or phenyithiacetyl, the aryl radical being unsubstituted or by methyl or chlorine may be substituted.
  • Alkyl or aralkyloxycarbonyl is preferably ethyl, isobutyl, tert-butyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl or 4-chlorobenzyloxycarbonyl.
  • the amino acid representing Y with a hydrophobic side chain can in particular be Ala, Val, Leu, Ile, Met, Phe, Pro, Tyr, Phg (C-phenylglycine), and also a hydrophobically substituted amino acid such as Ser (Bu t ), Thr (Bu t ), Cys (Bu t ), Cys (Et), Cys (Bzi), Glu (OBu t ), Asp (OBu t ), Glu (NH-Bu t ), Glu (NH-Et), Lys (Boc), Orn (Boc), Tyr (Bu t ), Tyr (Me), Phe (CI), Tyr (CI), and also alkyl, halogen or methoxy-substituted tryptophan.
  • a hydrophobically substituted amino acid such as Ser (Bu t ), Thr (Bu t ), Cys (Bu t ), Cys (Et), Cys (Bzi), Glu (OBu t ), Asp
  • Preferred alkyl amides are n-alkyl or branched alkyl amides such as isopropyl, isobutyl, tert-butyl, 3-methylbutyl or 3-ethylbutylamide; as aralkylamides, for example benzyl- or phenethylamide, which can be substituted in the core and / or in the side chain by 1 to 2 methyl groups.
  • the same alkyl, aryl or aralkyl radicals can also be present in an ester bond.
  • the peptides according to the invention are similar to the polypeptides of the formula R-Arg-Lys-Asp-Val-Tyr-R 'known from FR-A 2 408 580 and to a pentapeptide Arg recently described in Science 204 (1979), page 1309 -Lys-Asp-Val-Tyr, a partial sequence of thymopoietin, which is addressed as the region of this peptide which is said to be responsible for the biological action.
  • this sequence corresponds to the above-mentioned sequence basic-basic-acid-hydrophobic-hydrophobic, which thus appears as a superordinate principle for peptides of the thymic activity mentioned.
  • the peptides according to the invention contain L- or D-glutamic acid and D-aspartic acid or D-a-aminoadipic acid as the acidic amino acid.
  • Peptides of glutamic acid and a-aminoadipic acid are much more stable than aspartic acid peptides in a weakly acidic environment, in which these compounds are mostly used.
  • the latter are largely rearranged into isoasparagine peptides via asparaginimide peptides, so that e.g. heat sterilization of aspartic acid peptides is not possible.
  • the rearrangement also takes place at room temperature and even at refrigerator temperature at a noticeable rate. If the acidic D-amino acids stand for S, the enzymatic stability of the peptides is increased.
  • the compounds according to the invention also include tri- and tetrapeptide derivatives, the effect of which is in many cases the same or even increased compared to a pentapeptide of the sequence Lys-Lys-Glu-Val-Val produced according to the invention.
  • the invention further relates to a method for producing the peptides mentioned, which is characterized in that amino acid sequences of the formula in which A, B, S, X and Y have the meaning given in claim 1, is based on methods of peptide synthesis.
  • the peptides according to the invention have a significantly longer lifespan than the natural thymus peptides.
  • S is an acidic D-amino acid such as D-glutamic acid or D-a-aminoadipic acid.
  • the compounds according to the invention can be used to treat immunodeficiencies, viral and fungoid as well as chronic bacterial infections.
  • the invention is also the use of said peptides in general to influence the maturation of T - lymphocytes.
  • the residue is triturated successively with water, 1N citric acid, saturated sodium bicarbonate solution and water and dried.
  • To remove the protective groups dissolve in 25 ml of trifluoroacetic acid and the crude pentapeptide derivative is precipitated after 40 min with ether.
  • the trifluoroacetate obtained is converted into the acetate by stirring with a strongly basic ion exchanger in the acetate form in 50 percent methanol, which is present as a resinous semi-solid mass after filtering off the exchanger and distilling off the solvent.
  • the peptide-containing fractions are checked by thin layer chromatography, pooled and lyophilized. Yield of DC-uniform peptide-benzylamide acetate 10.4 g. Amino acid analysis: Glu 1.00, Val 1.87, Arg 1.99. No valine was found in the dansyl end group determination.
  • Example 1 The procedure of Example 1 is followed, except that 5.6 g of H-Val-Tyr-NH z , prepared according to Chem. Ber. 97 (1964), page 1197, and after removal of the protective groups and purification, receives 9.0 g of the title compound as acetate.
  • H-Val-Olpr ⁇ HCl prepared in a known manner by esterifying L-valine with HCl / isopropanol, are dissolved in 20 ml of dimethylacetamide with the addition of 4.0 ml of N-ethylmorpholine.
  • symmetrical Boc-valanhydride is produced from 13.1 g of Boc-Val-OH and 6.6 g of DCC in 50 ml of dimethylacetamide at 0 °.
  • the two solutions are combined, allowed to come to room temperature, stirred for a further 4 hours at about 22 ° and the solvent is distilled off in vacuo.
  • the residue is taken up in 150 ml of ethyl acetate and extracted three times with 20 ml of water.
  • the Boc compound is dissolved in 60 ml of trifluoroacetic acid. After 40 min, a precipitate is precipitated with ether / petroleum ether (1: 1), which is thoroughly digested with the same mixture. After drying in vacuo over KOH, the yield is 6.1 g, mp. 172-174 ° C. Elemental analysis (N, F) correct.
  • Isoleucine and HCl / isopropanol are prepared in a known manner from isoleucine isopropyl ester hydrochloride. 2.1 g of this compound are reacted and worked up analogously to Example 5 C) with 14.4 g of Adoc-Arg (Adoc) z- Arg- (Adoc) 2 -Glu (OBu t ) -OH ⁇ 2 H 2 O. Yield 6.2 g amino acid analysis: Glu 1.00, Ile 0.95, Arg 2.06.
  • the tert-butyl group is split off with trifluoroacetic acid analogously to Example 1, converted into the acetate and the compound is purified by chromatography on Sephadex IR ) LH 20. Yield 2.9 g, amino acid analysis: Glu 1.00, Val 1.89, Arg 2.01.
  • Example 12 The procedure of Example 12 is followed, but ZD-Lys (Boc) -ONSu is used. The crude product is catalytically hydrogenated in 90 percent acetic acid on Pd. Then, the procedure for cleavage of t Boc and Bu, for conversion into the acetate and subsequent purification in analogy to Examples 12 and 1. Yield 6.0 g. Amino acid analysis: Glu 1.00, Val 1.89, Lys 0.99, Arg 1.02.
  • the resinous residue is dissolved in 100 ml of methanol and hydrogenated catalytically on Pd with titration with 2N HCl in methanol at pH 4. After filtering off the catalyst, the mixture is brought to the dryene, the solid residue is taken up in 50 ml of dimethylformamide and 4.0 g of ethyl pentachlorophenyl carbonate (Bull. Soc. Chim. France 23 (1900), page 818) are added. The mixture is stirred overnight, the solvent is distilled off in vacuo and the residue is digested with ether. The procedure for removing the protective groups, converting them to acetate and for cleaning is analogous to Example 1. Yield 4.1 g. Amino acid analysis: Glu 1.00, Val 1.92, Lys 2.02.
  • Example 15 The procedure of Example 15 is followed, except that 1.1 g of succinic anhydride are used instead of the phthalic anhydride and the procedure is as described in Example 15. Yield 6.1 g. No free a-amino group can be recognized by the dansyl method.
  • the change in concentration in the eluate due to the emerging peptides is determined via the refractive index (differential refractometer). Yield after lyophilizing the fraction, redissolving in 5 percent acetic acid and again lyophilizing 0.6 g.
  • Amino acid analysis Glu 1.00, Val 1.88, s-guanidocaproyl not determined, ⁇ -aminocaproyl ⁇ 0.02, Arg 1.01.
  • the mixture is hydrogenated catalytically on Pd with titration with 2N methanolic HCl at pH 4, the reaction mixture is filtered off after the reaction has ended and the solution is brought to dryness. The solid residue is digested with ether and dried in vacuo. Mp 135-140 ° (Z). Elemental analysis (C, H, N, CI) correct. Yield 28.3 g.
  • the compound obtained according to B) is catalytically hydrogenated on Pd in 80 percent methanol.
  • the catalyst is filtered off and the solution is brought to dryness in vacuo. Trituration of the residue with ether leads to the chromatographically pure compound.
  • the ethyl acetate phase is then extracted with 150 ml of saturated NaHCO 3 solution, K 2 SO 4 / KHSO 4 solution, saturated NaH-CO 3 solution and water, dried over Na 2 SO 4 and concentrated.
  • Example 21 C 31 g H-Val-Val-OBu t ⁇ HCI analogous to Example 21 B) with 37 g of Z-Glu (OBzl) -OH in dimethylformamide in the presence of 13.5 g HOBt and 12.8 ml of N-ethylmorpholine by means of 22 g of DCC condensed.
  • catalytic hydrogenation is carried out as described in Example 21 C).
  • the ether-insoluble compound is isolated and is uniform by thin layer chromatography. Yield 51 g.
  • Example 21 D 6.8 g of Z-Lys (Z) -Lys (Z) -OH are preactivated according to Example 21 D) and reacted with 4.15 g of the compound obtained as above. Deprotection and purification are carried out analogously to Example 21 D. Yield 4.9 g. Amino acid analysis: Glu 1.00, Val 0.88, Ile 0.86, Lys 2.04.
  • Pd / carbon catalyst is added to a solution of 65 g (0.134 mol) of Z-Val-Tyr- (Bu t ) -OMe in 300 ml of methanol and the mixture is passed with stirring and with the addition of about 2N methanolic hydrochloric acid at pH 4.5 (autotitrator ) Hydrogen through the solution until methanolic hydrochloric acid is no longer absorbed.
  • the catalyst is then filtered off and the filtrate is concentrated. The residue is triturated with ether, the substance dissolving and crystallizing after standing overnight at 4 °. The crystals are filtered off and dried over P 2 O 5 .
  • the residue is dissolved in 100 ml of ethyl acetate.
  • the ethyl acetate phase is shaken out with 30 ml of KHSO 4 / K 2 SO 4 solution and with 50 ml of saturated NaHCO 3 solution, dried over Na 2 SO 4 and concentrated.
  • the residue is dissolved in petroleum ether and stored at 4 ° C. overnight. A white crystalline substance precipitates and is suctioned off. Yield 3.94 g, mp. 133 °.
  • the mother liquor is concentrated and the resulting oil (17.6 g) is chromatographed over 200 g of silica gel. First, elute with methylene chloride and finally with a mixture of methylene chloride and acetone such as 9: 1.
  • the substance is chromatographed on silica gel in the solvent mixture methylene chloride: methanol: water: acetic acid such as 90: 15: 2: 2. Yield 2.78 g (63%).
  • the amorphous residue was processed without characterization.
  • the precipitate is filtered off and washed with water.
  • the still water-moist product is distributed between 150 ml of ethyl acetate and 150 ml of water.
  • the still wet precipitate is dissolved in 200 ml of ethyl acetate.
  • the adhering water is separated.
  • the ethyl acetate phase is shaken out again with 50 ml of water, dried over Na 2 SO 4 and concentrated. It is overturned from ethyl acetate / petroleum ether.
  • Example 30 F Analogously to Example 30 F are Z-Glu (OBu t) -Ile-Tyr (Bu t) -O-cyclohexyl catalytically hydrogenated in 200 ml of methanol, 5 g (6.65 mmol). Yield 4.3 g (99%).
  • H H-Lys (Boc) -Glu (OBu t ) -Val-Tyr (Bu t ) -On-butyl.
  • the filtrate is concentrated in a high vacuum and the residue is partitioned between ethyl acetate and water.
  • the ethyl acetate phase is consecutively with sat. NaHCO 3 solution, KHSO 4 solution and water, extracted, dried over Na 2 SO 4 and concentrated.
  • the residue crystallizes from petroleum ether. Yield 5.96 g.
  • Example 38 E Analogously to Example 38 E are 1:57 g (2 mmol) of H-Lys (Boc) -D-Asp (OBu t) -Val-Tyr (Bu t) -OMe ⁇ HCl with 1.6 g (2.2 mmol) of Z-Arg (Z 2 ) -OTcp implemented and worked up analogously to Example 38A.
  • the substance is chromatographed over 80 g of silica gel.
  • the eluent is methylene chloride / acetone like 7: 3.
  • Example 38 A Analogously to Example 38 A are 4:04 g (12 mmol) ZD-Glu (OBu t) -OH condensed with 4.64 g (12 mmol) H-Val-Tyr (Bu t) -OMe HCI in 25 ml of dimethylformamide. Yield 6.72 g.
  • Example 38 B Analogously to Example 38 B, 5.4 g (8 mmol) of ZD-Glu (OBu t ) -Val-Tyr (Bu t ) -OMe are catalytically hydrogenated. The residue is dried in a high vacuum. Yield 4.57 g (100%). The substance is amorphous.
  • Example 38 C Analogously to Example 38 C are reacted with 4.76 g (8.5 mmol) of Z-Lys (Boc) -OTcp 4:57 g (8 mmol) of HD-Glu (OBu t) -Val-Tyr (Bu t) -OMe ⁇ HCl.
  • the substance is precipitated from the dimethylformamide solution with 250 ml of water, to which 10 ml of saturated NaHCO 3 solution are added.
  • the precipitate is filtered off and washed well with water and dried.

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Claims (12)

1. Peptide de formule
Figure imgb0019
dans laquelle
A représente l'arginine, la lysine, l'ornithine ou l'homoarginine, chacune en configuration L ou D, un groupe co-amino, ω-guanidino- ou ω-diméthyl- aminoalcanoyle ayant de 3 à 6 atomes de carbone et éventuellement un groupe a-amino en configuration D ou L, qui de son côté peut porter un groupe atcanoyfe ayant de 1 à 6 atomes de carbone, aroyle ayant de 7 à 11 atomes de carbone, cycloalcanoyle ayant jusqu'à 2 atomes de carbone dans la partie alcoyle et de 5 à 7 atomes de carbone dans la partie cycloalcoyle, un groupe aralca- noyle ayant au total jusqu'à 9 atomes de carbone, auquel cas un groupe -CH2- peut être remplacé par-O-ou-S-, un groupe alcoyl- ou aralcoyl-oxycarbonyle ayant jusqu'à 7 atomes de carbone ou un groupe succinoyle, succinamoyle, glutaroyle, glutaminyle, pyroglutamyle, phtaloyle, phtalamidyle ou 2-carboxybenzoyle,
B représente un acide aminé basique, de préférence la L-lysine, la L-arginine, la L-homoarginine ou la L-ornithine
X représente la L-valine ou la L-isoleucine et
Y représente un acide aminé de configuration L ou D, avec une chaîne latérale hydrophobe, dont la partie ester, amide, alcoylamide a de 1 à 6 atomes de carbone ou la partie aralcoylamide a de 7 à 10 atomes de carbone, un groupe alcoylamide ou alcoylester ayant de 1 à 6 atomes de carbone ou un groupe aralcoylamide ou aralcoylester ayant de 7 à 10 atomes de carbone,
S est Glu, D-Glu, D-Asp ou l'acide D-a-amino- adipique, et de leurs sels.
2. Peptide de formule
Figure imgb0020
dans laquelle
A représente l'arginine, la lysine, l'ornithine ou l'homoarginine, chacune en configuration L ou D, un groupe co-amino-, ω-guanidino- ou ω-diméthyl- aminoalcanoyle ayant de 3 à 6 atomes de carbone et éventuellement un groupe a-amino en configuration D ou L qui, de son côté, peut porter un groupe alcanoyle ayant de 1 à 6 atomes de carbone, aroyle ayant de 7 à 11 atomes de carbone, cycloalcanoyle ayant jusqu'à 2 atomes de carbone dans la partie alcoyle et de 5 à 7 atomes de carbone dans la partie cycloalcoyle, un groupe aral- canoyle ayant jusqu'à 9 atomes de carbone au total, auquel cas un groupe -CH2- peut être remplacé par -0- ou -S-, un groupe alcoyl- ou aralcoyl-oxycarbonyle ayant jusqu'à 7 atomes de carbone, ou un groupe succinoyle, succinamoyle, glutaroyle, glutaminyle, pyroglutamyle, phtaloyle, phtalamidyle ou 2 carboxybenzoyle,
B représente un acide aminé basique, de préférence la L-lysine, la L-arginine, la L-homoarginine ou la L-ornithine,
X représente la L-valine ou la L-isoleucine et
Y est un acide L- ou D-aminé avec une chaîne latérale hydrophobe dont la partie ester, amide, alcoylamide a de 1 à 6 atomes de carbone ou la partie aralcoylamide a de 7 à 10 atomes de carbone, un groupe alcoylamide ou alcoylester ayant de 1 à 6 atomes de carbone ou un groupe aralcoylamide ou aralcoylester ayant de 7,à10 atomes de carbone,
S est Glu, et de leurs sels.
3. Peptide de formule
Figure imgb0021
dans laquelle
A représente l'arginine, la lysine, l'ornithine ou t'homoarginine, chacune en configuration L ou D, un groupe ω-amino, ω-guanidino- ou ω-diméthyl- aminoalcanoyle ayant de 3 à 6 atomes de carbone et éventuellement un groupe a-amino en configuration D ou L, qui de son côté peut porter un groupe alcanoyle ayant de 1 à 6 atomes de carbone, aroyle ayant de 7à11 atomes de carbone, cycloalcanoyle ayant jusqu'à 2 atomes de carbone dans la partie alcoyle et de 5 à 7 atomes de carbone dans la partie cycloalcoyle, un groupe aral- canoyle ayant au total jusqu'à 9 atomes de carbone, auquel cas un groupe -CH2- peut être remplacé par -0- ou -S-, un groupe alcoyl- ou aralcoyl-oxycarbonyle ayant jusqu'à 7 atomes de carbone, ou un groupe succinoyle, succinamoyle, glutaroyle, glutaminyle, pyroglutamyle, phtaloyle, phtalamidyle ou 2-carboxybenzoyle,
B représente un acide aminé basique, de préférence la L-lysine, la L-arginine, la L-homoarginine ou la L-ornithine,
X représente la L-valine ou la L-isoleucine et
X représente un acide L- ou D-aminé avec une chaîne latérale hydrophobe dont la partie ester, amide ou alcoylamide a de 1 à 6 atomes de carbone ou la partie aralcoylamide a de 7 à 10 atomes de carbone, un groupe alcoylamide ou alcoylester ayant de 1 à 6 atomes de carbone, ou un groupe aralcoylamide ou aralcoylester ayant de 7 à 10 atomes de carbone,
S est D-Glu, D-Asp ou l'acide D-a-aminoadipi- que, auquel cas sont exclus des peptides de formule A-Lys-S-X-Y et A-D-Lys-S-X-Y, dans lesquels A représente l'arginine éventuellement substituée par un groupe alcanoyle en C,-C6 ou par Gin, l'homoarginine ou un groupe ω-guanidino-alcanoyle en C3-C6, et
Y représente simultanément Tyr ou D-Tyr, ainsi que leurs amides, alcoylamides en C,-C6 ou leurs ester d'alcoyle en C1-C6; et de leurs sels.
4. Peptide selon l'une des revendications 1 et 2, de formule Arg-Lys-Glu-Val-Trp-OMe.
5. Peptide selon l'une des revendications 1 et 2, de formule Arg-Lys-Glu-Val-Tyr-OMe.
6. Peptide selon l'une des revendications 1 et 2, de formule D-Lys-Arg-Glu-Val-Tyr-OMe.
7. Peptide selon la revendication 1, de formule Arg-Lys-D-Aad-Val-Tyr-OMe.
8. Peptide selon la revendication 1, de formule Arg-Lys-D-Glu-Val-Tyr-OMe.
9. Procédé de préparation de peptides selon l'une quelconque des revendications 1 à 8, caractérisé en ce qu'on construit des séquences d'acides aminés de formule
Figure imgb0022
dans laquelle A, B, S, X et Y ont les significations indiquées dans les revendications 1 à 8, selon des procédés de la synthèse des peptides.
10. Peptide selon l'une quelconque des revendications 1à8 pour utilisation comme agent pour influencer la maturation des lymphocytes T.
11. Peptide selon l'une quelconque des revendications 1à8 pour utilisation comme médicament.
EP80105158A 1979-09-22 1980-08-29 Peptides et procédé pour leur préparation Expired EP0025897B1 (fr)

Priority Applications (1)

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AT80105158T ATE6857T1 (de) 1979-09-22 1980-08-29 Neue peptide und verfahren zu ihrer herstellung.

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DE19792938420 DE2938420A1 (de) 1979-09-22 1979-09-22 Neue peptide und verfahren zu ihrer herstellung
DE2938420 1979-09-22

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EP0025897A3 EP0025897A3 (en) 1981-07-01
EP0025897B1 true EP0025897B1 (fr) 1984-03-28

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JP (1) JPS5653640A (fr)
AT (1) ATE6857T1 (fr)
AU (1) AU541852B2 (fr)
CA (1) CA1182448A (fr)
DE (2) DE2938420A1 (fr)
ES (1) ES8105700A1 (fr)
IL (1) IL61098A (fr)
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Publication number Priority date Publication date Assignee Title
DE3100974A1 (de) * 1980-01-18 1982-01-21 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente enthaltende arzneimittel mit immunregulierender wirkung, und thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente
US4309340A (en) * 1980-03-31 1982-01-05 American Home Products Corporation Polypeptide compositions
US4298523A (en) * 1980-06-17 1981-11-03 Ortho Pharmaceutical Corporation Methods and compositions for preparation of H-ARG-X-Z-Y-TYR-R
US4361673A (en) * 1980-09-19 1982-11-30 American Home Products Corporation Polypeptide compositions
EP0056594B1 (fr) * 1981-01-14 1984-09-12 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Fragments de thymosine alpha-1 et compositions pharmaceutiques à action immunorégulatrice qui les contiennent
HU185263B (en) * 1981-06-12 1984-12-28 Richter Gedeon Vegyeszet Process for producing peptides effective on the immuncontroll analogous with the tp5
DE3146598A1 (de) * 1981-11-25 1983-07-07 Hoechst Ag, 6230 Frankfurt "neue peptide und verfahren zu ihrer herstellung"
GB2130590B (en) * 1982-11-10 1986-01-08 Erba Farmitalia Peptides
US4505853A (en) * 1983-11-18 1985-03-19 Ortho Pharmaceutical Corporation Enzyme-resistant immunomodulatory peptides
DE3421614A1 (de) * 1984-06-09 1985-12-12 Hoechst Ag, 6230 Frankfurt Verfahren zur herstellung von pentapeptiden mit wirkung auf das immunsystem und zwischenprodukte dieses verfahrens
US4547489A (en) * 1984-06-11 1985-10-15 Ortho Pharmaceutical Corporation Conformationally restricted thymopentin-like compounds
US4629723A (en) * 1984-06-27 1986-12-16 Ortho Pharmaceutical Corporation Potent thymopentin analogs
AU583578B2 (en) * 1984-12-14 1989-05-04 Australian Commercial Research & Development Limited Amino acid and peptide inhibitors of human leucocytic elastase
HU199878B (en) * 1987-06-19 1990-03-28 Berlin Chemie Veb Process for producing acylated splenopentynes and pharmaceutical compositions comprising such compounds as active ingredient
NZ229004A (en) * 1988-05-19 1993-09-27 Immunobiology Res Inst Inc Tetrapeptides having t cell helper acitivity
JPH03502930A (ja) * 1988-09-30 1991-07-04 イミユノバイオロジー・リサーチ・インスチチユート・インコーポレーテツド Ｔ細胞のサプレツサー活性を有するペプチド
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US5837686A (en) * 1991-11-25 1998-11-17 Peptide Therapeutics Limited Peptides and antibodies for treatment of rheumatoid arthritis
CN101168560B (zh) * 2006-10-23 2012-09-05 江苏正大天晴药业股份有限公司 N-取代肽酰胺，其药物组合物与用途

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EP0018182A1 (fr) * 1979-04-12 1980-10-29 Ortho Pharmaceutical Corporation Peptides possédant une activité analogue à celle de la thymopoiétine, compositions pharmaceutiques qui les contiennent, et procédé pour les préparer

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FR2408581A1 (fr) * 1977-11-15 1979-06-08 Sloan Kettering Inst Cancer Composition de pentapeptide, son procede d'obtention et composition therapeutique en comportant
EP0018182A1 (fr) * 1979-04-12 1980-10-29 Ortho Pharmaceutical Corporation Peptides possédant une activité analogue à celle de la thymopoiétine, compositions pharmaceutiques qui les contiennent, et procédé pour les préparer

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EP0025897A2 (fr) 1981-04-01
AU6255080A (en) 1981-04-09
ZA805830B (en) 1981-09-30
IL61098A0 (en) 1980-11-30
CA1182448A (fr) 1985-02-12
JPS5653640A (en) 1981-05-13
EP0025897A3 (en) 1981-07-01
AU541852B2 (en) 1985-01-24
US4420424A (en) 1983-12-13
ES495088A0 (es) 1981-06-16
DE3067271D1 (en) 1984-05-03
DE2938420A1 (de) 1981-04-09
ATE6857T1 (de) 1984-04-15
IL61098A (en) 1984-09-30
ES8105700A1 (es) 1981-06-16

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